Retinoic acid‐metabolizing enzyme cytochrome P450 26a1 (cyp26a1) is essential for implantation: Functional study of its role in early pregnancy

Abstract

Vitamin A (VA) is required for normal fetal development and successful pregnancy. Excessive VA intake during pregnancy may lead to adverse maternal and fetal effects. Cytochrome P450 26A1 (cyp26a1), a retinoic acid (RA)-metabolizing enzyme, is involved in VA metabolism. It has been shown that cyp26a1 is expressed in female reproductive tract, especially in uterus. In order to investigate the role of cyp26a1 during pregnancy, we constructed a recombinant plasmid DNA vaccine encoding cyp26a1 protein and immunized mice with the plasmid. Compared to control groups, the pregnancy rate of the cyp26a1 plasmid-immunized mice were significantly decreased (P < 0.01). Further results showed that both cyp26a1 mRNA and protein were specifically induced in the uterus during implantation period and localized in the uterine luminal epithelium. Importantly, the number of implantation sites was also significantly reduced (P < 0.05) after the uterine injection of cyp26a1-specific antisense oligos or anti-cyp26a1 antibody on day 3 of pregnancy. Accordingly, the expression of RA-related cellular retinoic acid binding protein 1 and tissue transglutaminase was markedly increased (P < 0.05) in the uterine luminal epithelium after intrauterine injection treatments. These data demonstrate that uterine cyp26a1 activity is important for the maintenance of pregnancy, especially during the process of blastocyst implantation.

Retinoid Signaling is a Context-Dependent Regulator of Embryonic Stem Cells

“…are not among them, only the expression of the RA induced-RA eliminator Cyp26a1 is elevated, suggesting that RA signaling is not activated yet in this stage and the incidental RA level is actively cleared away. This is in correlation with the findings that presence of RA decreases the viability of blastocyst (Huang, Shen et al 2003) and explain the importance of uterine Cyp26a1 activity in the maintenance of pregnancy, especially during the process of blastocyst implantation (Han, Xia et al 2010). Potentially, an RA-independent, FGF signaling controlled Cyp26a1 expression may be responsible for this for RA clearance in day 4 EBs.…”

Differential Gene Expression Profiling of Mouse Uterine Luminal Epithelium During Periimplantation

“…[15][16][17][18][19][20] The morphological transformations are likely associated with the differential gene expression in the LE, for example, upregulation of gap junction protein b-2 (GJB2/ Cx26) in the LE likely contributes to the altered gap junction channels in the LE. 21 Differential gene expression of many genes in the periimplantation LE has been reported, such as cytochrome P450 26A1 (Cyp26a1), 22 Gjb2, 21 histidine decarboxylase (Hdc), 23 leukemia inhibitory factor receptor (Lifr), 24 lysophosphatidic acid receptor 3 (Lpar3), 25 msh homeobox 1 (Msx1), 26 myeloid differentiation primary response gene 88 (MyD88), 27 ethanolamine kinase 1 (Etnk1), 28 progesterone receptor (Pgr), [29][30][31] phospholipase A2, group IVA (Pla2g4a), Microarray analysis has been widely used to determine the gene expression profiling associated with implantation in the mouse uterus 30,35,36 and in the LE. 27,28,37 The LE cells represent only 5% to 10% of total uterine cells.…”

Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct

“…Therefore, RA was synthesized, and transcription by RAR was activated in the stroma of proximal and middle Müllerian ducts. Uterine CYP26A1 activity is important for blastocyst implantation in pregnant mice (32); however, Cyp26a1 expression was low in the Müllerian duct, suggesting that RA was not catabolized in the Müllerian duct. Expression of Dhrs9, Aldh1a1, and Cyp26b1 was confirmed in the adult uterus and/or vagina, and it was regulated during the estrous cycle or by E2 treatment (20)(21)(22).…”